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Abstract

Diabetic autonomic neuropathy (DAN) is a major complication of diabetes mellitus. Parasympathetic stimulation of the heart decreases the rate and force of contraction, the latter at least in part in response to inhibition of L-type Ca currents. SREBPs are transcription factors which regulate expression of enzymes involved in fatty acid and cholesterol synthesis. SREBP-1 expression is regulated by insulin. Here we present data demonstrating that ventricular myocytes from hearts of type I diabetic Akita mice demonstrate decreased carbamylcholine (Carb) inhibition of isoproterenol (Iso) stimulated L-Type Ca currents, that this effect is dependent on SREBP-1 and reversed by pretreatment of mice with pravastatin. Type I diabetic Akita mice 4 mo of age demonstrated serum glucose levels of >500 mg/dL. Iso stimulated L-Type Ca current in ventricular myocytes from Akita diabetic mice, determined by the whole cell clamp method, was increased 2.9 ±0.3 fold above basal value of 16.7 ±2.0 pA/pF which was not significantly different from that in cells from WT mice (2.6 ±0.3 fold). However, Carb inhibition (20 μM) of Iso stimulated L-Type Ca current was significantly attenuated in cells from Akita diabetic mice (27.9 ±4.8%, n=9), compared with 67.3 ±2.25%, (n=16) in WT mice (p<0.001). Insulin treatment of mice for 1 week reversed this effect, while normalization of glucose by pfloridzin had no effect. Adenoviral expression of SREBP-1 reversed the impaired Carb inhibition of Iso stimulated L-Type Ca current in cells from Akita mice to 70.0 ±3.4% (n=7), compared to 43.9 ±5% (n=9) in mice infected with empty virus (p<0.001). Pretreatment of mice for one month with pravastatin (20 mg/kg/day, I.P.) had no effect on Iso stimulated L-type Ca currents in cells from Akita mice, but restored the impaired Carb inhibition to 54.4±3.5% (n=17) compared with 30.1±2.7% in cells for saline treated Akita mice (p<0.001). These data are the first to demonstrate that SREBP-1 regulates parasympathetic inhibition of L-type Ca currents and that parasympathetic dysfunction in the diabetic heart might be reversed by statin treatment suggesting a new therapeutic approach to the treatment of DAN.